Genotype-phenotype correlation in British families with X linked congenital stationary night blindness

Abstract

Aim: To correlate the phenotype of X linked congenital stationary night blindness (CSNBX) with genotype.

Methods: 11 CSNB families were diagnosed with the X linked form of the disease by clinical evaluation and mutation detection in either the NYX or CACNA1F gene. Phenotype of the CSNBX patients was defined by clinical examination, psychophysical, and standardised electrophysiological testing.

Results: Comprehensive mutation screening identified NYX gene mutations in eight families and CACNA1F gene mutations in three families. Electrophysiological and psychophysical evidence of a functioning but impaired rod system was present in subjects from each genotype group, although the responses tended to be more severely affected in subjects with NYX gene mutations. Scotopic oscillatory potentials were absent in all subjects with NYX gene mutations while subnormal OFF responses were specific to subjects with CACNA1F gene mutations.

Conclusions: NYX gene mutations were a more frequent cause of CSNBX than CACNA1F gene mutations in the 11 British families studied. As evidence of a functioning rod system was identified in the majority of subjects tested, the clinical phenotypes "complete" and "incomplete" do not correlate with genotype. Instead, electrophysiological indicators of inner retinal function, specifically the characteristics of scotopic oscillatory potentials, 30 Hz flicker and the OFF response, may prove more discriminatory.

Figure 1

Scotopic perimetry (representative examples). Mean threshold elevation to a blue stimulus was 3.5 log units in the NYX group and 2.0 log units in the CACNA1F group, whilst that to a red stimulus was 2.0 and 1.9 log units, respectively.

Figure 2

Dark adaptation on curves: blue stimulus, retinal location −9, 9. (A) Subjects with NYX gene mutations. (B) Subjects with CACNA1F gene mutations.

Figure 3

Comparison of ERG waveforms between genotype groups. (A) A scotopic b-wave response to an SF-2.6 log unit stimulus was recorded in both CSNBX genotype groups but was of lower amplitude in the NYX group. (B) Responses of CSNBX subjects to an SF stimulus in dark adapted conditions showed the typical “negative wave” response. The waveform in the NYX group was smooth and devoid of the wavelets of the oscillatory potentials seen in the normal and CACNA1F mutation group. (C) Scotopic oscillatory potentials (OP) were unrecordable in the NYX group and subnormal in the CACNA1F mutation group. (D) The 30 Hz photopic waveform was saw toothed in the NYX group, and biphasic and subnormal in the CACNA1F response. (E) The ON (b-wave) response was subnormal in all CSNBX subjects. The OFF (d-wave) response was normal in the NYX subjects and borderline subnormal in both CACNA1F subjects tested.

Figure 4

Scatter plots of scotopic ERG responses. (NYX gene mutation group = CSNB1, CACNA1F gene mutation group = CSNB2). (A) Plot of b-wave amplitude to scotopic stimulus (B) Plot of b-wave amplitude to SF stimulus. (C) Plot of maximal OP amplitude.

Figure 5

Scatter plots of photopic responses. (A) Plot of photopic b-wave amplitudes (ON response). (B) Plot of d-wave amplitudes (OFF response).